α-amino acids present an important biological interest, because they constitute peptides and proteins. As they play an important role in the organism, the chemist seeks to synthesize structural analogous, in order to obtain new biological properties or modified peptides. The use of non-natural amino acids allow for example to conduct studies of metabolism and of enzymatic cycles. Non-natural amino acids are also implied in the development of new drugs.
Among different strategies to develop analogous of natural amino acids, it is possible to introduce an unsaturation on the lateral chain. The unsaturation may be more or less distant from the alpha carbon. In the present invention, the Applicant has focused his interest on γ,δ-unsaturated α-amino acids.
The introduction of an unsaturation into amino acids implies structural modifications that can induce new biological properties. Especially, peptide chains comprising an unsaturated amino acid present a rigid secondary structure with a β-turn configuration. Such a structure is interesting to develop new drugs or to improve the fixation of bioactive molecules. Consequently, unsaturated amino acids are important for the synthesis of modified peptides, useful in biology or in medicinal chemistry. Unsaturated amino acids may also be used to develop new markers useful in medical imaging or for diagnosis.
For example, β,γ-unsaturated α-amino acids such as trans-3,4-dehydroarginine or rhizobitoxine have been shown to be enzyme inhibitors.

Unsaturated amino acids have also been used for the preparation of antibiotics, such as Phomopsin (A), which is a hexapeptide constituted by two fragments. Fragment A is a cyclodedihydrotripeptide constituted only by non-classical amino acids whose β,γ-unsaturated L-Valine, and fragment B, which is a linear didehydrotripeptide with exocyclic framework.

Unsaturated amino acids may also have applications for the preparation of peptide derivatives useful as sweeteners, in polyamide materials, in nanomaterials, as surfactants or as phytosanitary products.
Amino acids bearing an unsaturation on the lateral chain are also used in organic synthesis, in particular in Diels-Alder reactions, in cyclo-additions or in catalytic reactions (hydroformylation, metathesis, Heck coupling, Suzuki-Miyaura coupling). Especially, metathesis reactions on unsaturated amino acids may be used to obtain higher unsaturated homologues.
Unsaturated amino acids may also be used in total synthesis of products of biological interest, as it is the case in the synthesis of Nothapodytine B, a compound useful as antiviral drug, or in the case of the synthesis of the α-amino-arachidonic acid, a fatty acid.
Moreover, unsaturated amino acids may be functionalized by transition metals and resulting complexes may be used as contrast agents for medicinal imaging, as therapeutic agents, as synthesis intermediates or as chiral catalysts.
The presence of a double bond on the lateral chain of amino acid offers the possibility to further functionalize the molecule with a wide variety of chemical groups, such as aryl, alkyl, calixarenyl, azido or boronato groups, and therefore to obtain numerous compounds useful in high throughput synthesis.
Among the syntheses of unsaturated amino acids described in the literature, allylation of Shiff base with creation of Cα-Cβ carbon bonds, catalyzed by palladium complex or under phase transfer conditions, is one of the methods the most used to access to such compounds (Scheme 1). This strategy allows the highly stereoselective synthesis of allylglycine derivatives, in the presence of an organocatalyst such as the ammonium salt depicted in Scheme 1. However, this method applies only to some allylic groups and it is mainly the Shiff base with a t-butyl ester that is employed. Therefore, this method is not versatile. Moreover, reactants and catalysts used in this method are expensive or difficult to prepare.

Other routes of synthesis of unsaturated amino acids are available, such as Mitsunobu reactions with hydroxyacid derivatives, beta-elimination reactions, the use of cuprozincic derivatives of serine or Strecker reaction. However, the syntheses require numerous steps with uncertain yields and unguaranteed stereoselectivities. Especially, these methods are often associated with loss of reagents and are dedicated to the synthesis of a single compound. Therefore, these methods are not adapted to the synthesis of series of compounds. In the case of cuprozincic derivatives of serine, the use of cuprozincic products is difficult, depends of the substrats and requires expertise in the manipulation of such reagents.
The synthesis of γ,δ-unsaturated amino acids has also been envisaged by Wittig reaction. However, up to now, few examples of Wittig reaction involving amino acid moiety were described. Indeed, the basic conditions of reaction cause racemization and are incompatible with the polyfunctionality of an amino acid, even protected.
One example of synthesis of unsaturated amino acids through a Wittig reaction involves aldehydes derived from aspartic or glutamic acid (Kokotos G., Padron J. M., Martin T., Gibbons W. A. and Martin V. S., J. Org. Chem., 1998, 63, 3741-3744).
In this synthesis, represented in scheme 2, a Wittig reaction between a phosphonium ylide and the aldehyde derived from glutamic acid affords, after deprotection of acid and amine functions, the enantiomerically pure α-amino-arachidonic acid in 88% yield.

Starting from aspartic acid instead of glutamic acid, this method may lead to γ,β-unsaturated amino acids. However, this strategy presents the inconvenient not to be versatile. Indeed, the introduction of different moieties after the double bond on the lateral chain of the amino acid requires the synthesis of each corresponding phosphonium salts. Therefore, this method is not adapted to synthesize a wide variety of unsaturated amino acid for high throughput synthesis.
An alternative method involving a Wittig reaction was proposed in a pioneering work of Itaya depicted in scheme 3 (Itaya T. and Mizutani A., Tetrahedron Lett., 1985, 26(3), 347-350). In this example, a phosphonium chloride was prepared in seven steps starting from L-serine. The phosphonium chloride was then reacted with an aldehyde, affording the corresponding β,γ-unsaturated amino acid with a yield of 5%, in a stereoselective manner.

In further work on the synthesis of this particular unsaturated amino acid implied in the synthesis of Wybutine, Itaya improved the yield of the Wittig reaction to modest yields (<30%) by some optimizations of the conditions (Itaya T, Mizutani A. and Lida T., Chem. Pharm. Bull., 1991, 39(6), 1407-1414).
Therefore the method developed by Itaya does not allow obtaining satisfying yields, as required in high throughput synthesis. Moreover, conditions used by Itaya are drastic and the reaction is performed in presence of HMPT, a solvent suspected to be mutagen.
Alternatives to Itaya method were proposed by Sibi and by Baldwin to use a Wittig reaction in the synthesis of unsaturated amino acids, starting from a phosphonium salt derivative of amino acid.
The method developed by Sibi consists in protecting the carboxylic acid function of the amino acid by reduction in alcohol, in order to avoid the deprotonation of the ester in the basic conditions of the Wittig reaction (scheme 4) (Sibi M. P. and Renhowe P. A., Tetahedron Lett., 1990, 31(51), 7407-7410; Sibi M. P., Rutherford D., Renhowe P. A. and Li B., J. Am. Chem. Soc., 1999, 121, 7509-7516). The L-serine is first protected into an oxazolidinone derivative with phosgene. The intermediate is then transformed into iodo-derivative after reduction, and finally in the phosphonium salt represented on scheme 4. After deprotonation of the phosphonium salt, the ylide reacts with aldehydes to afford the unsaturated derivatives which are then hydrolyzed into amino alcool. The β,γ-unsaturated amino acid is finally obtained after oxidation by pyridinium dichromate (PDC).

The inconvenient of the method developed by Sibi lies in the fact of using phosgene and a chrome oxidizing agent. On the other hand, this reaction leads to unsaturated amino acids with the inverse absolute configuration D. Consequently, the synthesis of unsaturated L-amino acids requires using D-serine which is very expensive.
The method of Baldwin to synthesize γ,β-unsaturated amino acids by Wittig reaction consists in reacting an aziridine derived from L-serine, successively with a stabilized ylide and with an aldehyde (Scheme 5) (Baldwin J. E., Adlington R. M. and Robinson N. G., JCS Chem. Corn., 1987, 153-155; Baldwin J. E., Spivey A. C., Schofield C. J. and Sweeney J. B., Tetrahedron, 1993, 43, 6309-6330).

One inconvenient of the synthesis developed by Baldwin lies in the fact that the adequately protected aziridine should first be synthesized. This preliminary step is not easy, all the more that the aziridine is not very stable. Moreover, the reaction implying an ylide stabilized by an ester function is not very general and lead to moderate yields. Another drawback of this method is the presence in all products of an ester group in γ-position.
Intramolecular Wittig reactions have also been described to yield substituted pyrroline derivatives starting from oxazolone compounds (Scheme 6) (Clerici, F.; Gelmi, M. L.; Pocar, D.; Rondene, R. Tetrahedron 1995, 51, 9985). In this method, oxazolone derivatives are first reacted with triphenylvinylphosphonium bromide to afford the intermediate phosphonium functionalized oxazolone derivatives through Michael addition. The quenching of the reaction with methanol and p-toluensulfonic acid as catalyst affords the corresponding acylamino methyl ester. In a second step, this latter phosphonium salt undergoes an intramolacular Wittig reaction to yield the expected pyrroline derivatives.

The phosphonium bromide used by Clerici et al. is a derivative of amino acid wherein the alpha carbon is quaternary, which promotes the cyclization by Thorpe Ingold effect. The conditions used for the Wittig reaction are harsch, with the use of a strong base and reflux conditions. These conditions are known to be racemizing conditions and there is nothing in this document relative to the stereoselectivity of the reaction.